1. Field of the Invention
The present invention relates to novel substituted amino or hydroxy alkyl-1,1-bisphosphonic acid compounds, processes for their preparation, pharmaceutical compositions containing them, and methods for their use as bone-affinity agents for delivering bone resorption or formation active drugs directly to the bone target site.
2. Brief Description of Disclosures in the Art
It is known that certain compounds exhibit an affinity for bone. In this context, an affinity for bone relates to the ability of the compound to bind to mineralized bone matrix with a tendency to accumulate in bone and to bind into the crystalline apatite structure. Tetracyclines, polymalonates and diphosphonates are representative compounds known to have an affinity for bone.
See, for example, U.S. Pat. No. 4,705,651 (assigned to Gentili) and U.S. Pat. No. 4,922,007 (assigned to Merck & Co. Inc.) which disclose the bone affinity agent, 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid and processes for its production.
It has previously been proposed to join a bone-seeking agent, such as tetracyline, to a carbonic anhydrase inhibitor through a bridging agent to provide compounds for the treatment or prophylaxis of degenerative bone diseases. See EP 201,057 (published Nov. 12, 1986).
Further, it is taught in Fujisawa's JO 2104-593A to link a hormone, e.g., calcitonin or insulin-like growth factor to an amino methylene bisphosphonic acid.
However, it is not taught or suggested in either reference that a hydroxyl containing steroidal hormone, such as 17-beta estradiol, norethandrolone, androsterone, norethindrone, or nandrolone, can be linked to an amino or hydroxy alkylidene bisphosphonic acid to produce an agent effective in treating bone disorders.